Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis

• Sponsor: Columbia University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01222260
• Collaborator: Cephalon (Industry)
• Enrollment: 40
• Locations: 6
• Arm: 1
• Actual Duration (Months): 78
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study is being done to see if the combination of bendamustine and dexamethasone will help people with amyloidosis that has returned after standard treatment, and to to estimate the partial hematologic response rate (PHR).

Condition or Disease	Intervention/Treatment	Phase
AL Amyloidosis	Drug: Bendamustine; Drug: Dexamethasone	Phase 2

Detailed Description

Systemic light-chain amyloidosis (AL) is a protein conformation disorder due to a clonal plasma cell dyscrasia. There are no established and approved second-line therapies for patients with systemic AL amyloidosis who fail initial melphalan-based treatment, be it high-dose melphalan with stem cell transplant or oral melphalan and dexamethasone (MDex). Therefore new treatments are needed for those who fail initial therapy and for those who initially respond but subsequently relapse.

Therapy of AL is generally based on treatment regimens used in multiple myeloma (MM). Bendamustine achieves partial response with relapsed/refractory MM. Based on this high anti-MM activity, we anticipate that bendamustine will also be very active in clonal plasma cell disorder associated with AL.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of the Combination of Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis
• Actual Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Mar 1, 2019
• Actual Study Completion Date: Jul 3, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment Arm Subjects with AL will receive Bendamustine and Dexamethasone

Drug: Bendamustine; Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study); Other Names: Bendamustine Hydrochloride Treanda ® ; Drug: Dexamethasone; 40 mg orally on days 1, 8, 15, 22 of each cycle; Other Names: Decadron

Outcome Measures

Primary Outcome Measures

1. Partial Hematologic Response (PHR) Rate [Up to 2 years]

   Only patients who have received at least 2 cycles of therapy are eligible for response assessment. The proportion of patients with PHR two months post-treatment will be estimated, with a 95% exact binomial confidence interval. Partial response is defined as the reduction of the difference between involved and uninvolved free light chains (dFLC) of ≥ 50% OR a reduction of ≥ 50% of the M-protein if M-spike is ≥ 0.5 g/dL.

Secondary Outcome Measures

1. Overall Hematologic Response Rate (OHR) [Up to 2 years]

   The proportion of response-evaluable patients experiencing OHR will be estimated, with a 95% exact binomial confidence interval. Overall hematologic response rate as defined by normalization of the free light chain levels and ratio, negative serum and urine immunofixation OR reduction in the difference between involved and uninvolved free light chains (dFLC) to <4 mg/dL.

2. Organ Response Rate (ORR) [Up to 2 years]

   The proportion of response-evaluable patients experiencing ORR will be estimated, with a 95% exact binomial confidence interval. Amyloid-related organ response will be evaluated on the basis of the accepted criteria described: Kidneys: 30% reduction or drop below 0.5 g in 24-hour urine protein excretion in the absence of progressive renal insufficiency. Heart: N-terminal pro b-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide response (>30% and >300 ng/L decrease in patients with baseline NT-proBNP ≥ 650 ng/L or New York Heart Association (NYHA) class response (≥ 2 class decrease in subjects with baseline NYHA class 3 or 4). Liver: 50% decrease of an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm. Neuropathy: improvement supported by clinical history, neurologic exam, orthostatic vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% of previous movements/day.

3. Median Overall Survival (OS) [Up to 2 years]

   Survival is assessed as time to death from first day of treatment The OS function for response-evaluable will be estimated using the product-limit (Kaplan-Meier) estimator, along with 95% confidence bounds. The median survival will be estimated from the survival function. The analysis will be repeated on all patients who receive any therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients aged ≥ 18 years old

• Histopathology of amyloidosis or light chain deposition disease based on detection by polarizing microscopy of green bi-refringent material in Congo red-stained tissue specimens or characteristic electron microscopy appearance or immunohistochemical stain with anti-light chain anti-sera

• Demonstrate measurable disease as defined by one or more of the following:

• Serum monoclonal protein ≥ 0.5 g/dL by serum electrophoresis

• Urine monoclonal protein > 200 mg/dL in a 24 hr urine electrophoresis

• Serum immunoglobulin free light chain ≥ 5 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio. The difference between involved and uninvolved free light chains should be ≥ 5 mg/dL (dFLC)

• Demonstrate clonal population of plasma cells in the bone marrow or immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Patients had at least one prior regimen consisting of at least 1 cycle

• If not previously transplanted, patient should be either ineligible for autologous stem cell transplantation (ASCT), or must have declined the option of ASCT. Patients who have previously had ASCT and have subsequently progressed are eligible, provided other entry criteria are met

• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

Patients must meet the following laboratory criteria:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

• Hemoglobin ≥ 9 g/dl (May transfuse packed red blood cells (PRBC) to meet parameter)

• Platelets ≥ 100x 10^9/L (Must be independent of platelet transfusion)

• Calculated creatinine clearance (CrCl) greater than or equal to 30 mL/min (Cockcroft-Gault Formula )

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN)

• Serum bilirubin <1.5 x ULN

• Serum potassium within normal limits

• Total serum calcium (corrected for serum albumin) or ionized calcium ≤ ULN

Exclusion Criteria:

• Patients meeting the criteria for symptomatic MM:

• Lytic lesions on skeletal survey or plasmacytoma

Patients meeting International Myeloma Working Group definition of symptomatic myeloma with symptoms only related to associated amyloidosis who would otherwise only meet the criteria for smoldering MM are potentially eligible

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or

• electrocardiographic evidence of acute ischemia or active conduction system abnormalities (not including 1st degree atrioventricular (AV)-block, Wenckebach type 2nd degree heart block, or left bundle branch block. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator or an authorized physician sub-investigator as not medically relevant). Note: There is no lower limit of left ventricular ejection fraction below which patients are excluded from participation.

• Patients with N-terminal (NT)-proBNP ≥ 1800nb/L or B-type natriuretic peptide (BNP) ≥ 400 ng/L, abnormal cardiac troponin T (cTnT) or cardiac troponin l (cTnI)

• Patient has received other investigational drugs within 14 days prior to enrollment

• Any form of secondary / familial amyloidosis

• Serious concurrent illness, which in the opinion of the investigator or an authorized physician sub-investigator would interfere with participation in this clinical study,

• Known HIV infection.

• Inability to provide informed consent or to comply with the schedule of office and treatment visits

• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women(woman not of child-bearing potential is defined as any woman whose menstrual periods have stopped in the past 12 consecutive months or have had a complete hysterectomy or both ovaries surgically removed).

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, low-risk prostate cancer, or cancer after curative treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tufts Medical Center	Boston	Massachusetts	United States	02111
2	Boston Medical Center	Boston	Massachusetts	United States	02118
3	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
4	Mt. Sinai Medical Center	New York	New York	United States	10023
5	Columbia University	New York	New York	United States	10032
6	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Columbia University
• Cephalon

Investigators

• Principal Investigator: Suzanne Lentzsch, MD, PhD, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 3, 2015

More Information

Publications

None provided.

• Responsible Party: Suzanne Lentzsch, MD, Associate Professor of Clinical Medicine, Columbia University
• ClinicalTrials.gov Identifier: NCT01222260
• Other Study ID Numbers: AAAJ7800; 10-012 (PRO10050217)
• First Posted: Oct 18, 2010
• Last Update Posted: Mar 30, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Suzanne Lentzsch, MD, Associate Professor of Clinical Medicine, Columbia University: Amyloidosis; Dexamethasone; Bendamustine; Relapsed AL Amyloidosis
• Additional relevant MeSH terms: Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Dexamethasone; Bendamustine Hydrochloride

Study Results

Participant Flow

Recruitment Details	Between January 2013 and March 2016, 40 patients were enrolled in the study and 31 patients were treated.

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with relapsed/refractory systemic light-chain (AL) will receive Bendamustine and Dexamethasone. Bendamustine: Patients will start bendamustine at dose level 0 and according to creatinine clearance (CrCl) on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Period Title: Overall Study
STARTED	31
COMPLETED	29
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Overall Participants	31
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	9 29%
Male	22 71%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 9.7%
White	15 48.4%
More than one race	0 0%
Unknown or Not Reported	13 41.9%
Time since diagnosis (months) [Median (Full Range) ]
Median (Full Range) [months]	31.0

Outcome Measures

1. Primary Outcome

Title	Partial Hematologic Response (PHR) Rate
Description	Only patients who have received at least 2 cycles of therapy are eligible for response assessment. The proportion of patients with PHR two months post-treatment will be estimated, with a 95% exact binomial confidence interval. Partial response is defined as the reduction of the difference between involved and uninvolved free light chains (dFLC) of ≥ 50% OR a reduction of ≥ 50% of the M-protein if M-spike is ≥ 0.5 g/dL.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Measure Participants	28
Count of Participants [Participants]	16 51.6%

2. Secondary Outcome

Title	Overall Hematologic Response Rate (OHR)
Description	The proportion of response-evaluable patients experiencing OHR will be estimated, with a 95% exact binomial confidence interval. Overall hematologic response rate as defined by normalization of the free light chain levels and ratio, negative serum and urine immunofixation OR reduction in the difference between involved and uninvolved free light chains (dFLC) to <4 mg/dL.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Measure Participants	28
Count of Participants [Participants]	16 51.6%

3. Secondary Outcome

Title	Organ Response Rate (ORR)
Description	The proportion of response-evaluable patients experiencing ORR will be estimated, with a 95% exact binomial confidence interval. Amyloid-related organ response will be evaluated on the basis of the accepted criteria described: Kidneys: 30% reduction or drop below 0.5 g in 24-hour urine protein excretion in the absence of progressive renal insufficiency. Heart: N-terminal pro b-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide response (>30% and >300 ng/L decrease in patients with baseline NT-proBNP ≥ 650 ng/L or New York Heart Association (NYHA) class response (≥ 2 class decrease in subjects with baseline NYHA class 3 or 4). Liver: 50% decrease of an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm. Neuropathy: improvement supported by clinical history, neurologic exam, orthostatic vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% of previous movements/day.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Measure Participants	24
Count of Participants [Participants]	7 22.6%

4. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Survival is assessed as time to death from first day of treatment The OS function for response-evaluable will be estimated using the product-limit (Kaplan-Meier) estimator, along with 95% confidence bounds. The median survival will be estimated from the survival function. The analysis will be repeated on all patients who receive any therapy.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
Measure Participants	28
Median (95% Confidence Interval) [months]	18.2

Adverse Events

Time Frame	2 years
Arm/Group Title	Treatment Arm
Arm/Group Description	Subjects with AL will receive Bendamustine and Dexamethasone Bendamustine: Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study) Dexamethasone: 40 mg orally on days 1, 8, 15, 22 of each cycle
All Cause Mortality
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)
Serious Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	10/29 (34.5%)
Cardiac disorders
Atrial fibrillation	1/29 (3.4%)	1
Gastrointestinal disorders
Diarrhea	1/29 (3.4%)	1
General disorders
Fatigue	1/29 (3.4%)	1
Infusion-related reaction	1/29 (3.4%)	1
Infections and infestations
Infection	1/29 (3.4%)	1
Fever and chills	2/29 (6.9%)	2
Renal and urinary disorders
Renal dysfunction	2/29 (6.9%)	2
Skin and subcutaneous tissue disorders
Rash	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	20/29 (69%)
Blood and lymphatic system disorders
Decreased lymphocyte count	6/29 (20.7%)	6
Decreased neutrophil count	3/29 (10.3%)	3
Decreased white blood cell count	2/29 (6.9%)	2
Anemia	2/29 (6.9%)	2
General disorders
Fatigue	8/29 (27.6%)	8
Hypotension	3/29 (10.3%)	3
Hypertension	3/29 (10.3%)	3
Syncope	3/29 (10.3%)	3
Nausea	2/29 (6.9%)	2
Renal and urinary disorders
Chronic kidney disease	4/29 (13.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.